1. Field of the Invention
The invention relates to compounds of formula I ##STR2##
in which R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(9), and B have the meanings indicated below, their preparation and their use, in particular in pharmaceuticals. The compounds affect the potassium channel opened by cyclic adenosine monophosphate (cAMP) or the I.sub.Ks channel and are outstandingly suitable as pharmaceutical active compounds, for example for the prophylaxis and therapy of cardiovascular disorders, in particular arrhythmias, for the treatment of ulcers of the gastrointestinal area or for the treatment of diarrheal disorders.
In pharmaceutical chemistry, in recent years the 4-acylaminochroman derivatives class has been worked on intensively. The most prominent representative of this class is cromakalim of the formula A (J. Med. Chem. 1986, 29, 2194). ##STR3##
Cromakalim and other related 4-acylaminochroman derivatives are compounds having a relaxant action on smooth muscular organs, so they are used for lowering raised blood pressure as a result of vascular muscle relaxation and in the treatment of asthma as a result of relaxation of the smooth musculature of the airways. It is common to all these preparations that they act at the cellular level, for example, of smooth muscle cells and result there in an opening of certain ATP-sensitive K.sup.+ channels. The increase in negative charge in the cell (hyperpolarization) induced by the efflux of K.sup.+ ions counteracts the increase in the intracellular Ca.sup.2+ concentration via secondary mechanisms and thus cell activation, which leads, for example, to muscle contraction.
The compounds of the formula I according to the invention differ from these acylamino derivatives structurally, inter alia, by the replacement of the acylamino group by a sulfonylamino function. While cromakalim (formula A) and analogous acylamino compounds act as openers of ATP-sensitive K.sup.+ channels, the compounds of the formula I according to the invention having the sulfonylamino structure, however, do not show any opening action on this K.sup.+ (ATP) channel, but surprisingly show a strong and specific blocking (closing) action on a K.sup.+ channel which is opened by cyclic adenosine monophosphate (cAMP) and differs fundamentally from the K.sup.+ (ATP) channel mentioned. More recent investigations show that this K.sup.+ (CAMP) channel identified in colonic tissue is very similar, perhaps even identical, to the I.sub.Ks channel identified in the cardiac muscle. In fact, the compounds of the formula I according to the invention were able to show a strong blocking action on the I.sub.Ks channel in guinea-pig cardiomyocytes and also on the I.sub.sK channel expressed in Xenopus oocytes. As a result of this blocking of the K.sup.+ (cAMP) channel or of the I.sub.Ks channel, the compounds according to the invention display pharmacological actions of high therapeutic utility in the living body.
Apart from the abovementioned cromakalim or acylaminochroman derivatives, compounds having a 4-sulfonylaminochroman structure, which, however, differ markedly from the compounds of the formula I according to the invention both in the structure and in the biological action, are also described in the literature. Thus EP-A-315 009 describes chroman derivates having a 4-phenylsulfonylamino structure, which are distinguished by antithrombotic and antiallergic properties. EP-A-389 861 and JP 01294677 describe 3-hydroxychroman or chromene derivatives having a cyclic 4-sulfonylamino group (e.g. compound B), which should act as antihypertensives via activation of the K.sup.+ (ATP) channels. EP-A-370 901 describes 3-hydroxychroman or chromene derivatives having a 4-sulfonylamino group, the remaining valency of the N atom bearing a hydrogen atom, which have CNS actions. Further 4-sulfonylaminochroman derivatives are described in Bioorg. Med. Chem. Lett. 4 (1994), 769-773: "N-sulfonamides of benzopyran-related potassium channel openers: conversion of glyburyde insensitive smooth muscle relaxants to potent smooth muscle contractors" and in FEBS Letters 396 (1996), 271-275: "Specific blockade of slowly activating I.sub.sK channels by chromanols . . . " and Pflugers Arch.--Eur. J. Physiol. 429 (1995), 517-530: "A new class of inhibitors of cAMP-mediated Cl.sup.- secretion in rabbit colon, acting by the reduction of cAMP-activated K.sup.+ conductance". ##STR4##